A variety of self-assembling particles have been used or proposed for drug delivery to a target site in a body. Lipid micellar particles formed of a surfactant provide certain advantages in solubilizing and delivering hydrophobic drugs, e.g., for intravenous drug delivery.
Liposome delivery systems have been employed for delivery of drugs to tissues and organs, e.g., liver and spleen, rich in macrophages of the reticuloendothelial (RES), for depot drug release in the bloodstream, and for site specific accumulation and drug release in solid tumors and sites of infection.
Liposomes offer a number of advantages over simpler micellar particles. The lipid bilayer shell in a liposome provides an internal aqueous compartment that is essentially isolated from bulk phase aqueous medium, allowing hydrophilic drugs to be sequestered at high concentration within liposomes, and further permitting loading of ionizable drugs by use of ion gradients across the liposomal membrane. Liposomes can also be processed to have selected sizes in the 30-200 nm size range for intravenous drug delivery. Finally, the outer liposome surfaces may be coated with a hydrophilic polymer, such as polyethylene glycol, to extend blood circulation time of the particles, and/or may be designed to carry surface-bound antiligand molecules for selective binding to target cells containing cell-specific surface ligands.
The use of synthetic polymers in drug delivery devices has focused on "smart polymers" a term given to polymers that form gels that have the ability to expand or contract in response to a specific stimulus, such as light, temperature or pH. Typically, such polymers will precipitate in solution or collapse with concomitant expulsion of gel pore contents. Synthetic polymers may be based on a number of types of monomeric units, including vinyl monomers, N-alkyl substituted acrylamides and the like. Copolymers have also been utilized in an attempt to combine or modulate the stimulus responsive properties of one or more known smart polymers. Polymer particles formed of negatively charged polymers have been designed for (i) rapid condensation (for drug entrapment) and decondensation (for drug release) or controlled-rate swelling and drug release, and (ii) high drug entrapment by an ion exchange mechanism.
The concepts of smart polymer particles and lipid-bilayer vesicles have been combined in drug-delivery particles of the type having a condensed-phase polymer core encased in a lipid-bilayer membrane, giving advantages of both types of drug-delivery systems. In particular, the polymer core of the particle can be loaded to high drug concentration, for rapid release by particle decondensation, and the lipid coating on the particles can be designed for targeting and/or for a target-specific triggering event which in turn leads to rapid particle decondensation.
It is evident that it is possible to design self-assembling lipid and/or polymer particles having various drug loading, targeting and triggering capabilities. Nonetheless, self-assembling particles of this type present two significant limitations. First, since the particles are typically spherical, the physical-contact area between the particles and target-site cells, for example, for particle binding to the cell, is more limited than would be the case with a particle having more planar surfaces. Secondly, and more importantly, the functioning of self-assembling particles, in terms of targeting and drug release, are limited in terms of (i) the particle materials (and therefore material properties) that can be employed, (ii) the types of drug storage and drug release mechanisms that can be realized, (iii) the number of targeting and therapeutic functions that can be built into the particles, (iv) the ability to place different functions at discrete locations on the particles, and (v) ability to be detected inside the body.
It is the purpose of the present invention to provide microdevices that significantly expand the shape, materials, and functions versatility and capabilities over self-assembling drug-delivery particles.